Vascular endothelial growth factor (VEGF) expression in murine lung model, has been associated with protection against hyperoxia-induced acute lung injury (HALl). Clinically, hyperoxia is commonly encountered in the management of individuals with respiratory failure. The biology of VEGF regarding angiogenesis and tumor growth has been extensively investigated, however, the protective role of VEGF in lung injury is not well understood. We have found that VEGF induces the expression of heme oxygenase-1 (HO-1) in lung tissue via Mitogen Activated Protein Kinases (MAPK's). HO-1 is protective in models of hyperoxic acute lung injury. We hypothesize that VEGF-mediated cytoprotection is largely via induction of HO-1 expression and its downstream effects. We will in AIM I: Characterize the regulation of HO-1 by VEGF in vivo and in vitro; in AIM II: Determine the contribution and mechanism of HO-1 in VEGF-mediated cytoprotection; in AIM III: Define the contribution of MAPK's to VEGF-induced HO-1 expression and HO-1 mediated cytoprotection. These investigations will provide insight into the cytoprotective effects of HO-1 and VEGF and mechanisms of protection from hyperoxic acute lung injury.